ABSTRACT Exposure to cigarette smoke has been associated with both childhood asthma and adult COPD, and may be a key early-life environmental link impacting trajectories of fixed airflow obstruction in asthmatics and COPD. The initiation of chronic obstructive lung disease pathways and networks may occur in utero and/or during early life. The identification of common epigenetic marks between asthma and COPD and the potential fetal origins of molecular susceptibility may represent biomarkers of and/or susceptibility factors for COPD and asthma. We hypothesize that fixed airflow obstruction is associated with variability in miRNA and DNA methylation in bronchial epithelium, that genetic and epigenetic variation act together to define susceptible individuals and that a subset of genes demonstrating epigenetic perturbations in fixed airflow in asthmatics and COPD will be associated in fetal lung tissue exposed to in utero smoke, supporting common and developmental origins of fixed airflow obstruction and COPD. We propose gene-level and network-based analysis of miRNA and DNA methylation sequencing data. In Aim 1, we will use state-of-the-art next generation sequencing approaches in DNA and RNA from BE cells from 175 subjects to identify gene-specific DNA methylation and miRNA marks associated with fixed airflow obstruction in asthmatics and older smokers with COPD, followed by an assessment of significant marks in utero tobacco smoke (IUS) exposed fetal lung tissue. We will perform genome-wide analysis of bronchial epithelial (BE) cell marks from asthmatic subjects, COPD subjects, and adult smokers without lung disease. In Aim 2 we will integrate genetic and epigenetic variation to assess genetic regulation of epigenetic marks and phenotypic outcomes. We anticipate that these genetic-epigenetic signatures will identify a subset of childhood asthmatics at risk for early irreversible airflow obstruction and COPD. We will integrate methylation and miRNA signals with gene expression to assess for potential functional relevance of identified networks, and network conservation between asthma, COPD and fetal lung tissue exposed to IUS. In Aim 3, we will assess the functional features of genes identified through methylome and miRNA sequencing using in vitro gene knockdown or overexpression in BE cells, to highlight genes with a functional impact on fixed AO through airway remodeling via pro-inflammatory and pro-fibrotic mediators. In summary, this project will investigate DNA sequencing-identified methylation and miRNA marks and networks associated in asthma and COPD and replicated in fetal lung tissue to identify common pathogenesis pathways and potential fetal origins or epigenetic susceptibility. Integrating genetic, epigenetic and gene expression data may identify key overlapping pathways that influence these major smoking-related pulmonary disorders and may provide an early-life biomarker to inform primary prevention of both asthma and COPD.